The present invention relates to a method for preventing or treating elevated blood lipid level-related diseases such as hyperlipidemia, arteriosclerosis, angina pectoris, stroke and hepatic diseases in mammals, which comprises by administering thereto an effective amount of rutin and/or quercetin.
It has been reported that blood lipids, especially cholesterols and triglycerides, are closely related to various kind of diseases such as coronary cardio-circulatory diseases, e.g., arteriosclerosis and hypercholesterolemia, and fatty liver. Cholesterol, a fatty steroid alcohol, is a blood lipid produced from saturated fat in the liver. Triglycerides are another type of blood lipids which are known to increase the risk of various diseases. It has also been reported that an elevated blood or plasma cholesterol level causes the deposition of fat, macrophages and foam cells on the wall of blood vessels, such deposit leading to plaque formation and then to arteriosclerosis (see Ross, R., Nature, 362, 801-809(1993)). One of the methods for decreasing the plasma cholesterol level is alimentotherapy to reduce the ingestion of cholesterol and lipids. Another method is to inhibit the absorption of cholesterol by inhibiting enzymes involved therein.
Acyl CoA-cholesterol-o-acyltransferase(ACAT) promotes the esterification of cholesterol in blood. Foam cells are formed by the action of ACAT and contain a large amount of cholesterol ester carried by low density lipoproteins. The formation of foam cells on the wall of artery increases with the ACAT activity, and, accordingly, an inhibitor of ACAT may also be an agent for preventing arteriosclerosis. Further, it has been reported that the blood level of LDL-cholesterol can be reduced by inhibiting the ACAT activity (see Witiak, D. T. and D. R. Feller (eds.), Anti-Lipidemic Drugs: Medicinal, Chemical and Biochemical Aspects, Elsevier, pp159-195 (1991))
Further, it has been reported that hypercholesterolemia can be treated effectively by reducing the rate of cholesterol biosynthesis through the inhibition of cholesterol ester transfer protein (CETP) which mediates the cholesterol transfers between the lipoproteins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase which mediates the synthesis of mevalonic acid, an intermediate in the biosynthesis of sterols or isoprenoids (see Cardiovascular Pharmacology, William W. Parmley and Kanu Chatterjee Ed., Wolfe Publishing, pages 8.6-8.7, 1994).
Therefore, numerous efforts have been made to develop medicines to inhibit HMG-CoA reductase; and, as a result, several compounds derived from Penicillium sp. and Aspergillus sp. have been commercialized. Specifically, Lovastatin(copyright) and Simvastatin(copyright) developed by Merck Co., U.S.A., and Pravastatin(copyright) developed by Sankyo Co., Japan, have been commercialized (see C. D. R. Dunn, Stroke: Trends, Treatment and Markets, SCRIPT Report, PJB Publications Ltd., 1995).
However, these medicines are very expensive and a long-term administration thereof is known to induce an adverse side effect to the central nervous system. Further, although Lovastatin(copyright) and Simvastatin(copyright) may reduce the plasma LDL cholesterol level by enhancing the activity of LDL receptor in the liver, they cause side effects such as increase in creatine kinase in the liver and rhabdomyloysis (see Farmer, J. A., et al., Baillers-clin. Endocrinol. Metal., 9, 825-847 (1995)). Accordingly, there has continued to exist a need to develop an inexpensive and non-toxic inhibitor of HMG-CoA reductase.
Another example of the elevated blood-lipid level-related disease is fatty liver. In particular, the excessive intake of fat-containing foods and alcohol causes fatty liver wherein a large amount of lipids is deposited in the liver tissue and the levels of serum GOT (glutamate-oxaloacetate transaminase), GPT (glutamate-pyruvate transaminase) and xcex3-GTP (xcex3-glutamyl transpeptidase) are elevated (see T. Banciu et al., Med. Interne., 20, 69-71(1982); and A. Par et al., Acta. Med. Acad. Sci. Hung., 33, 309-319(1976)).
Fat accumulates in the liver mainly in the form of triglycerides and fatty acids, and also to a minor extent in the form of cholesterol. Further, it has been reported that one of the major signs of fatty liver is high blood cholesterol and/or triglyceride contents. Therefore, fatty liver is closely related to the level of cholesterol and/or triglycerides in the blood.
Bioflavonoids are polyphenolic antioxidants which exist widely in the natural world, especially in vegetables, fruits, wine and the like. Hertog et al. have reported that the high uptake of rutin and quercetin may reduce the heart diseases-related death rate of old aged patients (see M. G. L. Hertog et al., Dietary antioxidant flavonoids and risk of coronary heart disease, Lancet. 342:1007-1011, 1993).
It has been reported that the bioflavonoids exhibit various useful pharmacological activities such as anti-inflammatory, capillary reinforcing, anti-oxidative, anti-cancer, anti-viral and anti-platelet aggregation activities (see O. Benavente-Garcia et al., Uses and properties of citrus flavonoids, J. Agr. Food Chem., 45, 4506-4515, 1997). Rutin, a glycosylated quercetin, is decomposed to quercetin by the action of microorganisms and absorbed in the intestines (see C. Manach et al., Bioavailability, metabolism, and physiological impact of 4-oxo-flavonoids. Nutrition Research 16:517-544, 1996).
Representative bioflavonoids, which can be found in citruses, are listed in Table I.
Rutin is also known to be effective in treating high protein edema (see U.S. Pat. No. 5,096,887); and quercetin has anti-cancer and anti-viral activities (see Japanese Patent Laid-open Patent Publication No. 4-234320).
The present inventors have endeavored to develop a novel pharmacological use of bioflavonoids which are abundantly present in herbs, foodstuffs, vegetables and fruits. As a result, it has been discovered that rutin and quercetin are effective in treating or preventing elevated blood lipid level-related diseases. Specifically, they can greatly reduce plasma cholesterol level; prevent the activities of HMG-CoA reductase and ACAT; inhibit the accumulation of macrophage-lipid complex on the endothelial wall of an artery in a mammal; and prevent hepatic dysfunctions in a mammal.
Accordingly, it is an object of the present invention to provide a such as hyperlipidemia, arteriosclerosis, angina pectoris, stroke and hepatic diseases in a mammal,
Accordingly, it is a primary object of the present invention to provide a method for treating or preventing an elevated blood lipid level-related disease in a mammal.
In accordance with one aspect of the present invention, there is provided a method for treating or preventing an elevated blood lipid level-related disease in a mammal, which comprises administering thereto an effective amount of rutin, quercetin or a mixture thereof.